CN102483405A - Biomarker for selecting patients and related methods - Google Patents
Biomarker for selecting patients and related methods Download PDFInfo
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- CN102483405A CN102483405A CN2010800311621A CN201080031162A CN102483405A CN 102483405 A CN102483405 A CN 102483405A CN 2010800311621 A CN2010800311621 A CN 2010800311621A CN 201080031162 A CN201080031162 A CN 201080031162A CN 102483405 A CN102483405 A CN 102483405A
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Abstract
The present invention concerns biomarkers and use thereof for determining whether a subject is or is not susceptible to developing a prophylactic or therapeutic immune response after such treatment.
Description
The present invention relates to field of immunology, particularly to the patient being carried out immunization therapy by for example infecting caused disease or cancer.More specifically, the present invention relates to be used for after this kind immunization therapy, predict whether the patient is easy to produce preventative or therapeutic is replied, preferably the method for immune response.The present invention relates to through immunogenic composition, particularly therapeutic vaccine improves the method and composition of patient's to be treated survival rate.
The routine immunization technology knows that for the people it relates to introduces antigen (like peptide, protein) in animal system for a long time, but this antigen induce immune response, thus said animal is provided to the for example protection of infection.These technology also comprise exploitation live vaccine and inactivated vaccine.Live vaccine generally is the avirulence form through attenuation of infector, can cause the immune response to the pathogenic form of this infector.
Many research groups also after deliberation vaccine as purposes to the potential therapeutic modality of multiple cancer types.The particular type of this vaccine strategy is commonly referred to as immunization therapy.
In recent years, the research and development of recombinant vaccine, particularly live recombined vaccines have obtained progress, wherein vector encoded and expression purpose exogenous antigen.Wherein, shown very promisingly based on the carrier of recombinant virus, and in the exploitation of novel vaccine, played a significant role.To many virus researches its express ability from the protein of foreign pathogens or tumor tissues, and induce ability in vivo to the specific immune response of these antigens.These vaccines based on gene generally can stimulate body fluid and cellullar immunologic response efficiently, and viral vectors possibly all be an efficient strategy for delivery of antigens encoding gene and promotion and enhancement antigen are presented.For as vaccine carrier, desirable viral vectors should be safe, and can efficiently present required pathogen specific antigen to immune system.In addition, carrier system must satisfy the standard that it can large-scale production that makes.Therefore, some viral vaccine carriers have appearred at present, they according to the application that is proposed all have relative advantage and limitation (summary of recombinant viral vaccine is consulted like Harrop and Carroll, 2006, Front Biosci., 11,804-817; Yokoyama etc., 1997, J Vet Med Sci., 59,311-322).
Observe the DNA carrier in vivo after the direct transfection zooblast in phase earlier 1990s, carried out a large amount of research and developed through the DNA that directly in animal, introduces coding for antigens based on using the DNA plasmid to come the immunity inoculation technology of induce immune response.These technology that are commonly referred to as the dna immunization inoculation have been used for causing protective immune response at a large amount of disease models at present.The summary of dna vaccination is consulted Reyes-Sandoval and Ertl, 2001 (Current Molecular Medicine, 1,217-243).
Yet, be to identify in the individuality of inoculation, to induce enough strong immune response to avoid infecting the means with disease in the general issue in vaccine field, thereby prolongation suffers from the for example patient's of cancer the survival of mortality disease with protection and/or treatment.
Therefore, carry out the oxadiazole derivatives as comt inhibitors that extensive work finds that some critical aspects through stimulating immune system plays a role in recent years, be used to improve vaccine-induced immune response.As if most these compounds (being called immune response modifier (IRM) or adjuvant) all pass through the fundamental immunity system mechanism, induce multiple important cytokine (for example interferon, interleukin, TNF etc. via Toll appearance acceptor (TLR).Consult like Schiller etc., 2006, Exp Dermatol., 15, biosynthesizing 331-341) plays a role.These compounds have shown stimulates the rapid cell factor that some T cell, dendritic cells or monocyte/macrophage are derived that discharges; Can also stimulate lymphocyte function, for example the antibody that in the antiviral and antitumor activity of IRM compound, plays a significant role of B emiocytosis.
Alternatively, the immunity inoculation strategy has been proposed, wherein most schemes that are based on initiation-booster immunization inoculation.According to the immunization scheme of these " initiation-reinforcements ", at first immune system is induced through the patient is used triggering composition, strengthen (consulting) through second composition of using reinforcement then like EP1411974 or US20030191076.
In addition, shown that in the health care background a kind of treatment maybe be only effective in the patient of particular group.Therefore hope to make them can customize the tool and method of best personalized patient therapy for the doctor provides; Promptly indicate suitable therapy so that higher treatment success ratio to be provided at reasonable time to suitable patient, monitoring improves pharmaceutical efficacy and security to the reaction of treatment; Elimination is to patient's unnecessary treatment (to the inappropriate therapy of patient); Reduce patient's unnecessary toxicity and spinoff, reduce the expense of the unnecessary or dangerous invalid medicine of patient and insurance company, and improve patient's quality of life; Finally make cancer become controlled disease, and according to circumstances follow-up is measured.
In this, document has proposed multiple tool and method, for example:
-pharmacogenetics, it comprises according to the research of hereditary difference to the individual reaction of medicine.These reactions relate to medicine and how in any given individuality, to bring into play function, and how it is by metabolism, its toxicity and dosage requirement.Along with the development of the Human Genome Project, pharmacogenetics has been expanded as pharmacogenomics.Pharmacogenomics has surmounted pharmacogenetics, possibly in drug discovery and exploitation, target discovery and affirmation and clinical testing, play a role.
-also can use metabolism group (Metabolomics) in the prospective medicine field.Genic pharmacogenetics is different with being confined to, and the drug metabolism group can be not only based on inherent cause but also based on non-genetic factor, the other drug in patient's body for example, the individual reaction to medicine of health status that the patient is present or the like prediction.
-biomarker has more and more important effect in therapeutic clinical development.Biomarker can be normal biological process, lysis or the indicator of pharmacological reaction that treatment is intervened.Its reach is from dividing into groups to patient colony to help to identify respondent and non-responder, to measure the effectiveness of treatment.Biomarker can be used as valuable instrument be used to better to make a strategic decision with the expense that reduces drug development with make treatment be applied to optimal patient colony quickly.
The invention provides and use biological markers (biomarker (biomarker)) prediction to relate to the patient is used material and the method that the treatment of immunogenic composition (being the immunotherapy treatment) is renderd a service, said biomarker confirmed be and the relevant believable basically signal of expection clinical effectiveness.Before with the treatment of said immunogenic composition, biomarker is present in the biological sample that obtains from the patient.The ability of the clinical effectiveness of predicted treatment makes clinician and patient can identify invalid treatment before treatment beginning, to the decision-making of knowing the inside story of associated treatment process, comprises whether abandoning or allow to implement alternative therapy.
The applicant has identified instrument and the immunity inoculation strategy that makes new advances at present.More specifically; The ratio that the present invention relates to interleukin 10/interferon gamma (IL10/IFN γ) is replied as the preventative or therapeutic whether the prediction patient is easy to produce through using immunogenic composition, preferably the purposes of the biomarker of immune response.Alternatively, according to the present invention, can (ratio of IFN γ/IL10) be as biomarker, but under the sort of situation, should change conclusion with interferon gamma/interleukin 10.
Van den Boogaardt etc., 2006 (Transplantation, 82,844-848) shown that (IFN γ/IL10) ratio is the valuable instrument of distinguishing for non-rejection of kidney transplant and rejection patient to interferon gamma/interleukin 10.
Jamal etc., 2007, (Tuberculosis, 87,279-287) be presented in the outer tuberculosis of lung and lung, interferon gamma/interleukin 10 (has direct relation between ratio of IFN γ/IL10) and the disease severity grade.
Similarly, Gomes-Silva etc., 2007, (Clinical and Experimental Immunology, 149,440-444) show that high IFN γ and low IL10 are associated with the severity of mucous membrane leishmaniasis.
According to first embodiment, the present invention relates to treat the method for patient's human diseases through using immunogenic composition, wherein said patient is selected from the patient crowd who is made up of the patient with low IL10/IFN γ ratio.
Therefore, the present invention relates to treat the method for patient's human diseases, said method comprising the steps of through using immunogenic composition:
-patient of selection in the patient crowd who forms by patient with low IL10/IFN γ ratio,
-selected patient is used said immunogenic composition.
According to another embodiment, the present invention relates to through using immunogenic composition, the prediction patient whether is easy to produce preventative or therapeutic is replied, the method for immune response preferably, said method comprises step:
-obtain blood sample from the patient;
-in said blood sample, measure IL10 and IFN γ level and
-calculating IL10/IFN γ ratio, wherein low IL10/IFN γ ratio explanation prediction patient is to producing preventative or therapeutic is replied, and preferably immune response has the neurological susceptibility of increase.
According to another embodiment, the present invention relates to through using immunogenic composition, select to be easy to produce preventative or therapeutic is replied, the patient's of immune response method preferably, said method comprises step:
-obtain blood sample from the patient;
-in said blood sample, measure IL10 and IFN γ level and
-calculating IL10/IFN γ ratio, wherein low IL10/IFN γ ratio explanation patient is to producing preventative or therapeutic is replied, and preferably immune response has the neurological susceptibility of increase.
According to another embodiment, the present invention relates to predict whether the patient is easy to energetically comprising that the treatment of using immunogenic composition produces the method for replying, and said method comprises step:
-obtain blood sample from the patient;
-in said blood sample, measure IL10 and IFN γ level and
-calculating IL10/IFN γ ratio, wherein low IL10/IFN γ ratio explanation prediction patient is to producing preventative or therapeutic is replied, and preferably immune response has the neurological susceptibility of increase.
According to another embodiment, the present invention relates to select be easy to energetically comprising that the treatment of using immunogenic composition produces the patient's who replys method, said method comprises step:
-obtain blood sample from the patient;
-in said blood sample, measure IL10 and IFN γ level and
-calculating IL10/IFN γ ratio, wherein low IL10/IFN γ ratio explanation patient is to producing preventative or therapeutic is replied, and preferably immune response has the neurological susceptibility of increase.
According to another embodiment, the present invention relates to test patient and whether will produce the stripped method (ex-vivo method) that therapeutic is replied comprising the methods of treatment of using immunogenic composition, wherein method of testing comprises step:
-obtain blood sample from the patient;
-in said blood sample, measure IL10 and IFN γ level and
-calculating IL10/IFN γ ratio, wherein low IL10/IFN γ ratio explanation patient will produce preventative or therapeutic is replied to immunogenic composition, preferably immune response.
Whether according to another embodiment, the present invention relates to test patient can be to producing the stripped method that therapeutic is replied through using immunogenic composition treatment method for cancer, and wherein method of testing comprises step:
-obtain blood sample from the patient;
-in said blood sample, measure IL10 and IFN γ level and
-calculating IL10/IFN γ ratio, wherein low IL10/IFN γ ratio explanation patient will produce therapeutic to the treatment method for cancer and reply.
The invention still further relates to and comprise the stripped method of using immunogenic composition; Wherein method of testing comprises that step is: measure IL10 and INF γ at the biological sample from the patient; Level in the blood sample especially; Calculate IL10/IFN γ ratio, wherein low IL10/IFN γ ratio explanation patient will produce preventative or therapeutic is replied to immunogenic composition, especially immune response.
According to another embodiment; The present invention relates to through using immunogenic composition the method that in patient induce immune response (being the immune response that is produced) is used to treat human diseases, wherein said patient is selected from the patient crowd who is made up of the patient with low IL10/IFN γ ratio.
According to another embodiment; The present invention relates to induce in the patient through using immunogenic composition immune response (being the immune response that is produced) at least one antigen to be used to treat the method for human diseases, wherein said patient is selected from the patient crowd who is made up of the patient with low IL10/IFN γ ratio.
According to another embodiment; The present invention relates to through using immunogenic composition the method that in patient induce immune response (being the immune response that is produced) is used to treat human diseases, wherein said patient is selected from the patient crowd that is made up of the patient with low IL10/IFN γ ratio and the immune response of wherein said generation is an innate immune responses.Innate immune responses is to comprise perhaps " APC " initiation of antigen presenting cell to the initial immune defense of health of pathogen and by various kinds of cell.The surface and the cytosol receptor of the molecule (for example, bacterium and viral nucleic acid, protein, carbon water composition) in these cellular expression identification external source sources.After detecting these signals; BMDC and macrophage have caused defense replys, and comprises the release to the chemotactic factor (CF) of attacking the position of cell factor (comprising interferon, TNF-α and IL-12) and attraction cell such as immature BMDC, macrophage, NK cell and granulocyte.Therefore, when health was producing adaptability and replys, innate immune responses had been given non-specific protection.
Therefore, the present invention relates to through using immunogenic composition the method that in patient induce immune response (being the immune response that is produced) is used to treat human diseases, said method comprising the steps of:
-patient of selection in the patient crowd who forms by patient with low IL10/IFN γ ratio,
-selected patient is used said immunogenic composition.
According to another embodiment, the present invention relates in the patient, induce immune response (being the immune response that is produced) to be used to treat the method for human diseases at least a antigen through using immunogenic composition, said method comprising the steps of:
-patient of selection in the patient crowd who forms by patient with low IL10/IFN γ ratio,
-selected patient is used said immunogenic composition.
According to another embodiment; The present invention relates to through using immunogenic composition the method that in patient induce immune response (being the immune response that is produced) is used to treat human diseases; The wherein said immune response that produces is an innate immune responses, said method comprising the steps of:
-in the patient crowd who forms by patient, select the patient with low IL10/IFN γ ratio,
-selected patient is used said immunogenic composition.
According to another embodiment, the present invention relates to through using immunogenic composition the method that in patient induce immune response (being the immune response that is produced) is used to treat human diseases, said method comprising the steps of:
-in the patient, measure the level of IL10 and IFN γ,
-calculate IL10/IFN γ ratio and
If-said patient has low IL10/IFN γ ratio, the patient is used said immunogenic composition.
According to another embodiment, the present invention relates in the patient, induce immune response (being the immune response that is produced) to be used to treat the method for human diseases at least a antigen through using immunogenic composition, said method comprising the steps of:
-in the patient, measure the level of IL10 and IFN γ,
-calculate IL10/IFN γ ratio and
If-said patient has low IL10/IFN γ ratio, the patient is used said immunogenic composition.
According to another embodiment; The present invention relates to through using immunogenic composition the method that in patient induce immune response (being the immune response that is produced) is used to treat human diseases; The immune response of wherein said generation is an innate immune responses, said method comprising the steps of:
-in the patient, measure the level of IL10 and IFN γ,
-calculate IL10/IFN γ ratio and
If-said patient has low IL10/IFN γ ratio, the patient is used said immunogenic composition.
In the application's full text, term singulative (" a " and " an ") uses with the implication of expression " at least one ", " one or more " or " a plurality of " said composition or step, only if its context has explanation in addition.For example, term " cell " comprises a plurality of cells, comprises its potpourri.More specifically, " at least one " and " one or more " be meant and be equal to or greater than 1 number, particularly 1,2 or 3.
The whole terms that use among this paper " and/or " include " with ", " or " and the implication of " whole or any other combination of the key element that said term is connected ".
The term " about " that this paper uses is illustrated within 20%, preferably within 10%, more preferably within 5%.For clearly, having added " about x " is the occurrence that comprises x.
Term " patient ", " experimenter " refer to the member of vertebrate, particularly mammalian species, include but are not limited to domestic animal, sports animal, primate (comprising the people).
The term " treatment " that this paper uses comprises and preventing and/or treating.Therefore, immunogenic composition of the present invention or method are not limited only to treatment and use, and can be used for prophylactic applications.This is contained by " produce preventative or therapeutic immunization is replied " in the literary composition." prevention " is not limited only to prevent the disease (like infectious diseases) that takes place immediately from also comprising the long-term consequence that prevents these infection, for example sclerosis or cancer.
" effective dose " of reactive compound or " capacity " are the amounts that is enough to realize result's (comprising clinical effectiveness) of useful or expectation.Effective dose can be used in single or divided doses." treatment effective dose " is to realize the amount of useful clinical effectiveness, includes but are not limited to alleviate one or more symptoms and the prevent disease (for example one or more symptoms of prevention infection) relevant with virus infections.
Term " patient who in the patient crowd who is made up of the patient with low IL10/IFN γ ratio, selects " be to be understood that to being meant: patient's the interleukin 10 and the level of interferon gamma are like disclosed herein the measurement, and it has low IL10/IFN γ ratio.When the patient's of test quantity greater than 1 the time, said patient forms patient crowd.
According to concrete embodiment, term " patient that therapeutic is replied " or " to treating the patient who replys energetically " mean the survival rate (consulting the embodiment part) that said patient has increase.
In the preferred embodiment of the invention, method of the present invention comprises initial step, and it is before using immunogenic composition, in from patient's biological sample, to measure interleukin 10 and interferon gamma level.
According to the present invention, in the level that obtains in patient's biological sample, to measure interleukin 10 and interferon gamma.Biological sample is including, but not limited to other fluid samples, solid tissue's sample of blood and biogenetic derivation, such as the biopsy sample.In preferred embodiments, biological sample is blood, blood plasma or serum, and it is simple relatively and be the Noninvasive operation to obtain sample from the patient in the case.The method of obtaining blood or serum is known in this field, is not a part of the present invention.
In addition, the several different methods of detection and quantitative polypeptide comprises instantaneous biomarker, is known.These class methods are including, but not limited to the method based on antibody, more specifically based on monoclonal antibody method.Detect with the concrete grammar of quantitative biomarker inessential for the present invention.Material for example of the present invention and method can be used Luminex technology (Luminex Corporation; Austin, Tex) or enzyme linked immunosorbent assay (ELISA) (ELISA, many ELISA kits are commercially available; For example, through CliniScience, Diaclone, Biosource).
According to one embodiment of the invention, the level of interleukin 10 and interferon gamma is through using TPPA.
According to a specific embodiment of the present invention, said one or more antibody are that IL10 or IFN γ are specific.
According to a specific embodiment of the present invention, said antibody is monoclonal antibody.
According to a specific embodiment of the present invention, for example through fluorescence, radioactive label, enzyme, biotin, perhaps arbitrary other method spike, the cell that has been intended to make mark said antibody is detectable to said antibody.These technology are widely-used and known in this area.
Be included in the level of measuring interleukin 10 and interferon gamma in patient's body before the patient used immunogenic composition in the said method of related fields; Calculate IL10/IFN γ ratio; Said IL10/IFN γ ratio and cutoff value (cut-off value) are compared; And based on predicting the effectiveness that immunotherapy is treated with cutoff value IL10/IFN γ ratio levels relatively.
According to specific embodiment, said cutoff value is about 5, preferably about 4, more preferably about 3 and particularly preferably about 2.According to an embodiment preferred, said cutoff value is about 3.7, and more preferably is 3.7.According to embodiment preferred, " low IL10/IFN γ ratio " indication IL10/IFN γ ratio is about below 5 according to the present invention, preferably about below 4 and more preferably about below 3 and especially about below 2.According to an embodiment preferred, about below 3.7, and more preferably be below 3.7 according to " low IL10/IFN γ ratio " according to the invention indication IL10/IFN γ ratio.According to embodiment preferred; Through enzyme linked immunosorbent assay (ELISA) (ELISA), through Luminex
analyze, through the chip lab system, through radiommunoassay or use antibody or other specific moleculars, based on the other system measurement interleukin 10 of the specific molecular identification of IL10 and IFN γ and the level of interferon gamma.
Term " immunogenic composition ", " vaccine combination ", " vaccine " or the interchangeable use of similar term that this paper uses; Refer to such medicament; It is suitable for stimulating/induce/improve patient's immune system; To alleviate current illness, for example improve survival rate, perhaps protection avoids or reduces current or injury or infection (comprising virus, bacterium, parasitic infection) in the future; For example reduce the duplicating or propagating in the patient of tumor cell proliferation or survival, reduction pathogen, perhaps can reduce the undesired symptom relevant, prolongation patient's survival rate with detecting with illness.Said immunogenic composition can contain all or part of of (i) at least a target antigen at least, and/or (ii) at least a recombinant vector of expressing all or part of (heterologous nucleotide sequence of all or part of of at least a target antigen of particularly encoding) of at least a heterologous nucleotide sequence in vivo.According to an alternate embodiment, immunogenic composition of the present invention comprise (iii) separately or with (i) and/or the (ii) at least a immune response modifier of combination.The instance of these immune response modifiers (IRM) comprises that the CpG oligonucleotides (consults like US 6,194,388; US2006094683; WO 2004039829), lipopolysaccharides, polyinosine: the poly complex (Kadowaki etc., 2001, J.Immunol.166,2291-2295) and known polypeptide and protein of inducing dendritic cells and/or monocyte/macrophage to produce cell factor.Other instances of these immune response modifiers (IRM) are organic molecules; For example immidazoquinolinaminas (imidazoq uinolinamine), imidazopyridine amine (imidazopyridineamines), 6; The naphthenic base imidazopyridine amine (cycloalkylimidazopyridineamine) that 7-condenses, imidazo naphthyridines amine (imidazonaphthyridine amine),
azoles and quinolinamine (oxazoloquinoline amine), thiazole and quinolinamine (thiazoloquinoline amine) and 1; The immidazoquinolinaminas of 2-bridge joint (is consulted like US 4; 689,338; US 5,389, and 640; US 6,110,929 with US 6,331,539).In another embodiment, immunogenic composition comprises stimulates patient's immune response with treatment disease, the for example cell of cancer.Said cell can be an antigen presenting cell, the dendritic cells that for example combine with antigen compsn (Provenge that is for example developed by Dendreon Corporation), tumour cell (GVAX that is for example developed by Cell Genesis) or lymphocyte.
The term " antigen " that this paper uses refers to and can comprise complicated antigen (the for example cell of tumour cell, virus infections, dendritic cells etc.) as any material of the target of immune response.For example, antigen can be the target of the cell-mediated and/or HI that produces of patient.Term " antigen " comprises all or part of of for example viral antigen, tumour specific antigen or tumor associated antigen, bacterial antigens, parasite antigen, allergen etc.:
-viral antigen comprises as from following antigen: first, second, third, fourth and HEV, HIV, herpesviral, cytomegalovirus, varicella zoster, papillomavirus, Epstein-Barr virus, influenza virus, parainfluenza virus, adenovirus, Coxsackie virus, Pironavirus, rotavirus, Respiratory Syncytial Virus(RSV), poxvirus, rhinovirus, rubella virus, papovavirus (papovirus), mumps virus, measles virus; Some limiting examples of known viruse antigen comprise as follows: from the antigen of HIV-1, and for example tat, nef, gp120 or gp160, gp40, p24, gag, env, vif, vpr, vpu, rev or its part and/or combination; From herpes virus hominis's antigen, for example gH, gL, gM, gB, gC, gK, gE or gD or its part and/or combination or from the early protein immediately of HSV1 or HSV2 for example ICP27, ICP47, ICP4, ICP36; From the antigen of cytomegalovirus (particularly human cytomegalovirus), for example gB or derivatives thereof; From the antigen of Epstein-Barr virus, gp350 or derivatives thereof for example; From the antigen of varicella virus, gp1,11,111 and IE63 for example; From the antigen of hepatitis virus, like hepatitis B, hepatitis C or hepatitis E virus antigen (for example the envelope protein E1 of HCV or E2, core protein, NS2, NS3, NS4a, NS4b, NS5a, NS5b, p7 or its part and/or combination); From the antigen of HPV (HPV6 for example, 11,16,18, like L1, L2, E1, E2, E3, E4, E5, E6, E7 or its part and/or combination); Antigen from other viral pathogens; Respiratory syncytial virus (RSV) (like F and G albumen or derivatives thereof) for example; Parainfluenza virus, measles virus, mumps virus, Flavivirus (like flavivirus, dengue fever virus, tick-brone encephalitis virus, Japanese encephalitis virus) or influenza virus cell (HA for example; NP, NA or M albumen, or its part and/or combination);
-tumour specific antigen or tumor associated antigen include but are not limited to cancer, lymthoma, enblastoma, sarcoma and leukaemia.The more specifically instance of these cancers comprises breast cancer, prostate cancer, colon cancer, squamous cell carcinoma, ED-SCLC, non-small cell lung cancer, human primary gastrointestinal cancers, cancer of pancreas, spongioblastoma, cervical carcinoma, oophoroma, liver cancer, carcinoma of urinary bladder, hepatoma, colorectal cancer, carcinoma of endometrium, salivary-gland carcinoma, kidney, liver cancer, carcinoma of vulva, thyroid cancer, liver cancer and polytype head and neck cancer, the carcinoma of the rectum, chromoma, laryngocarcinoma, prostate cancer.Cancer antigen is the antigen that can stimulate tangible tumour-specific immune response potentially.In these antigens some are by normal cell coding (but not necessarily expressing).These antigens can be characterized by in normal cell the antigen of usually reticent (promptly not expressing), only with the low expression level or the antigen of expressing in some stage of differentiation, and the antigen of temporal expression, for example EA and fetal antigen.Other antigens are by the cytogene coding of sudden change, for example oncogene (for example active ras oncogene), suppressor (the for example p53 of sudden change), the fusion that produced by inside disappearance or chromosome translocation.Other cancer antigens can be encoded by viral gene, the antigen that for example carries on RNA and the DNA tumour virus.Some limiting examples of tumour-specific or tumor associated antigen comprise MART-1/Melan-A; Gp100; DPP IV (DPPIV); ABP (ADAbp); Cyclophilin b (cyclophilin b); Colorectum related antigen (CRC)-C017-1A/GA733; Carcinomebryonic antigen (CEA) and immunogenicity epi-position CAP-1 and CAP-2; Etv6; Aml1; PSA (PSA) and immunogenicity epi-position PSA-1 thereof; PSA-2 and PSA-3; PSMA (PSMA); TXi Baoshouti/CD3-ζ chain; MAGE family tumor antigen (MAGE-A1 for example; MAGE-A2; MAGE-A3; MAGE-A4; MAGE-A5; MAGE-A6; MAGE-A7; MAGE-A8; MAGE-A9; MAGE-A10; MAGE-A11; MAGE-A12; MAGE-Xp2 (MAGE-B2); MAGE-Xp3 (MAGE-B3); MAGE-Xp4 (MAGE-B4); MAGE-C1; MAGE-C2; MAGE-C3; MAGE-C4; MAGE-C5); GAGE family tumor antigen (GAGE-1 for example; GAGE-2; GAGE-3; GAGE-4; GAGE-5; GAGE-6; GAGE-7; GAGE-8; GAGE-9); BAGE; RAGE; LAGE-1; NAG; GnT-V; MUM-1; CDK4; Tyrosinase; P53; MUC family (for example MUC-1); HER2/neu; P21ras; RCAS1; Alpha-fetoprotein; The E-cadherin; α-Lian albumen; Beta-catenin and γ-Lian albumen; P120ctn; Gp100.sup.Pmel117; PRAME; NY-ESO-1; Cdc27; Adenomatous polyposis coli albumen (APC); Fodrin; Connect protein 37; The Ig-idiotype; P15; Gp75; GM2 and GD2 gangliosides; NA (EBNA)-1, the former phosphatase of cerebrose, SSX-1, SSX-2 (HOM-MEL-40), SSX-1, SSX-4, SSX-5, SCP-1 and the CT-7 and the c-erbB-2 of viral product such as human papilloma virus toxalbumin, Smad family tumor antigen, lmp-1, P1A, EBV coding;
-bacterial antigens comprise as from following antigen: the mycobacterium that causes TB and leprosy, pneumatocele; Aerobic Gram-negative bacillus, mycoplasma, staphy lococcus infection, streptococcal infection, salmonella, Chlamydia, Neisseria;
-other antigens comprise like the antigen from malaria, leishmaniasis, trypanosomiasis, toxoplasmosis, snail fever, filariasis;
-allergen refers in responsive patient, to cause the material that allergia or asthma are replied.Allergenic tabulation very extensively can comprise pollen, insect venom, animal scurf, fungal spore and medicine (like penicillin).The allergenic instance of natural animal and plant includes but are not limited to the specific albumen of subordinate: canid (domesticated dog (Canis familiaris)); Dermatophagoides (Dermatophagoides) (for example, dust mite (Dermatophagoides farinae)); Felis (Felis) (domestic cat (Felis domesticus)); Ambrosia (Ambrosia artemiisfolia; Lolium (Lolium) (for example, English ryegrass (Lolium perenne) or Itanlian rye (Lolium multiflorum)); Cryptomeria (Cryptomeria) (Japanese cedar (Cryptomeria japonica)); Alternaria (Alternaria) (chain lattice spore (Alternaria alternata)); Alder; Alder (European alder (Alnus gultinoasa)); Betula (Betula verrucosa); Oak belongs to (Quercus) (white oak (Quercus alba)); Olea (Olea) (olive (Olea europa)); Artemisia (Artemisia) (argy wormwood (Artemisia vulgaris)); Plantago (Plantago) (for example ribwort (Plantago lanceolata)); Parietaria (Parietaria) (for example Parietaria officinalis or Parietaria judaica); Blattaria (Blattella) (for example Groton bug (Blattella germanica)); Apis (Apis) (for example Apis multiflorum); Cupressus (Cupressus) (for example cupressus sempervirens (Cupressus sempervirens), green dried cypress (Cupressus arizonica) and cupressus macrocarpa (Cupressus macrocarpa)); Juniperus (Juniperus) (for example Juniperus sabinoides, Juniperus virginiana, hackmatack (Juniperus communis) and A Xi Chinese juniper (Juniperus ashei)); Thuya (for example Thuya orientalis); Chamaecyparis Space (Chamaecyparis) (for example Japanese cypress (Chamaecyparis obtusa)); Periplaneta (Periplaneta) (for example American cockroach (Periplaneta americana)); Agropyron (Agropyron) (for example couchgrass (Agropyron repens)); Secale (Secale) (for example rye (Secale cereale)); Triticum (Triticum) (for example common wheat (Triticum aestivum)); Orchardgrass (Dactylis) (for example orchardgrass (Dactylisglomerata)); Festuca (Festuca) (for example meadow fescue (Festuca elatior)); Annual bluegrass belongs to (Poa) (for example English grass (Poa pratensis) or Canada blue grass (Poa compressa)); Avena (Avena) (for example oat (Avena sativa)); Holcus (Holcus) (for example yorkshire fog grass (Holcus lanatus)); Anthoxanthum (Anthoxanthum) (for example chrysanthemum thatch (Anthoxanthum odoratum)); Oatgrass (Arrhenatherum) (for example tall oat grass (Arrhenatherum elatius)); Agrostis (Agrostis) (for example white bent (Agrostis alba)); Ladder forage spp (Phleum) (for example timothy grass (Phleum pratense)); Reed canary grass belongs to (Phalaris) (for example reed canary grass (Phalaris arundinacea)); Paspalum (Paspalum) (for example Paspalum notatum); Sorghum (for example stone thatch Chinese sorghum (Sorghum halepensis)); And Brome (Bromus) (for example awnless brome (Bromus inermis)).
According to a specific embodiments, said antigen is encoded by heterologous nucleotide sequence, and is expressed in vivo by recombinant vector.
In an especially preferred embodiment, all or part of of one or more following antigens of heterologous nucleotide sequence of the present invention coding: HBV-PreS1, PreS2 and surface-coating albumen, core and polHIV-gp120 gp40, gp160, p24, gag, pol, env, vif, vpr, vpu, tat, rev, nef; HPV-E1, E2, E3, E4, E5, E6, E7, E8, L1, L2 (consulting) like WO 90/10459, WO 98/04705, WO 99/03885; HCV envelope protein E1 or E2, core protein, NS2, NS3, NS4a, NS4b, NS5a, NS5b, p7 (consulting) like WO2004111082, WO2005051420; Muc-1 (consults like US 5,861,381; US6,054,438; WO98/04727; WO98/37095).
According to modification more of the present invention, said immunogenic composition contains at least two kinds of antigens, the heterologous nucleotide sequence of at least two kinds of antigens of perhaps encoding, perhaps at least two kinds of heterologous nucleotide sequence of at least two kinds of antigens of coding, or its combination in any.
According to another specific embodiments, all or part of of said heterologous nucleotide sequence coding HPV antigen of the present invention, the early stage code area of E6 that said HPV antigen is selected from HPV, the early stage code area of E7 and derivant or the combination of HPV.
The coded HPV antigen of recombinant vector of the present invention is selected from HPV E6 polypeptide, HPV E7 polypeptide, and HPV E6 polypeptide and HPV E7 polypeptide are perhaps arranged simultaneously.The present invention includes use with p53 combine change or significantly reduced at least any HPV E6, and/or use and Rb combine change or significantly reduced at least any HPV E7 polypeptide (Munger etc., 1989, EMBO J.8,4099-4105; Crook etc., 1991, Cell 67,547-556; Heck etc., 1992, Proc.Natl.Acad.Sci.USA 89,4442-4446; Phelps etc., 1992, J.Virol.66,2148-2427).A kind of non-oncogene HPV-16E6 variant that is applicable to the object of the invention has lacked the one or more amino acid residues that are positioned at about 118 to about 122 (first methionine residues of the natural HPV-16E6 polypeptide of+1 representative), especially preferably lacks 118 to 122 residues (CPEEK) fully.A kind of non-cancer HPV-16E7 variant that is applicable to the object of the invention has lacked the one or more amino acid residues that are positioned at about 21 to about 26 (first amino acid of the natural HPV-16E7 polypeptide of+1 representative), especially preferably lacks 21 to 26 residues (DLYCYE) fully.According to an embodiment preferred, be used for the early stage polypeptide of one or more HPV-16 of the present invention through further modifying, improving I class MHC and/or II class MHC presents, and/or stimulate anti-HPV immunity.HPV E6 and E7 polypeptide are nucleoprotein, have shown before that film is presented can improve its treatment and render a service (consulting like WO99/03885).Therefore, it is desirable the early stage peptide modified one-tenth anchor of at least a HPV on cell membrane.The film anchor and can sequence (if lack this sequence in the natural polypeptides, then mixing secretion sequence, i.e. signal peptide) and easily realize through in the early stage polypeptide of this HPV, mixing the film anchor.Sequence by the film anchor and secretion sequence is known in the art.In brief, secretion sequence is present in and is positioned on the film or the N end of the polypeptide of secretion, and initial its through endoplasmic reticulum (ER).They contain 15 to 35 usually and are hydrophobic amino acid basically, remove through the specificity endopeptidase that is positioned on the ER thereafter, obtain mature polypeptide.The film anchor sequence and is generally high hydrophobicity matter, and be used for polypeptide be anchored on cell membrane (consult like Branden and Tooze, 1991, Introduction to Protein Structure p.202-214, NY Garland).
Can be used for selection that the contextual film anchor of the present invention sequence and secretion sequence very extensively.They can derive from any film anchor that comprises it and polypeptide and/or secrete polypeptide (for example cell or virus polypeptide), and for example rabies glycoproteins, HIV viral envelope glycoprotein and/or measles virus F albumen perhaps can synthesize.Sequence by film anchor in the used early stage HPV-16 polypeptide of insertion the present invention and/or secretion sequence can have common or different sources.The N end downstream that preferred site of inserting secretion sequence is a translation initiation codon, what the film anchor sequence then is the C end, for example is right after the terminator codon upper reaches afterwards.
The HPV E6 polypeptide that the present invention uses the preferably secretion through inserting measles F albumen and film anchor signal and is modified.Randomly or with its in combination, the HPV E7 polypeptide that the present invention uses the preferably secretion through inserting rabies glycoproteins and film anchor signal and is modified.
Can also improve the treatment of recombinant vector through the nucleic acid that uses one or more coding immunopotentiating agent polypeptide renders a service.For example, can be advantageously with the early stage polypeptide of HPV be connected such as following polypeptide: calprotectin (Cheng etc., 2001; J.Clin.Invest.108,669-678), Much's bacillus heat shock protein (HSP70) (Chen etc., 2000; Cancer Res.60,1035-1042), ubiquitin (Rodriguez etc., 1997; J.Virol.71,8497-8503) or bacteriotoxic translocation domain, for example pseudomonas aeruginosa exotoxin A (ETA (dIII)) (Hung etc.; 2001Cancer Res.61,3698-3703).
According to another embodiment preferred, recombinant vector of the present invention comprises the nucleic acid of above-mentioned one or more early stage polypeptide of coding (particularly early stage E6 of HPV-16 and/or HPV-18 and/or E7 polypeptide).
According to another concrete preferred embodiment, all or part of or derivatives thereof of said heterologous nucleotide sequence coding MUC1 antigen of the present invention.
According to another specific embodiments, all or part of of said one or more following antigens of heterologous nucleotide sequence coding of the present invention: HCV envelope protein E1 or E2, core protein, NS2, NS3, NS4a, NS4b, NS5a, NS5b, p7 or derivatives thereof.According to another specific embodiments, said one or more fusions of heterologous nucleotide sequence coding of the present invention, wherein configuration is a non-natural: at least one NS polypeptide occurs with the order that is different from native configurations.Therefore, if this fusion comprises NS3 polypeptide, NS4A polypeptide and NS5B polypeptide, then native configurations will be NS3-NS4A-NS5B, and NS3 holds at N, and NS5B holds at C.On the contrary, the non-natural configuration can be NS5B-NS3-NS4A, NS5B-NS4A-NS3, NS4A-NS3-NS5B, NS4A-NS5B-NS3 or NS3-NS5B-NS4A.Particularly, fusion of the present invention comprises following at least a:
Zero directly merges with the N of NS3 polypeptide end or the NS4A polypeptide through the joint fusion;
Zero directly merges with the N of NS5B polypeptide end or the NS3 polypeptide through the joint fusion;
Zero directly merges with the N of NS5B polypeptide end or the NS4B polypeptide through the joint fusion;
The directly fusion or pass through the joint fusion of the zero NS4A polypeptide that directly merges with the N of NS3 polypeptide end or merge through joint, the N end of said NS3 polypeptide and NS4B polypeptide; And/or
The directly fusion or pass through the joint fusion of the zero NS3 polypeptide that directly merges with the N of NS4B polypeptide end or merge through joint, the N end of said NS4B polypeptide and NS5B polypeptide.
In these specific parts of fusion of the present invention, each NS polypeptide can be natural independently or modify.For example, the NS4A polypeptide that comprises in the NS4A-NS3 part can be natural, and that the NS3 polypeptide comprises in the following modification is at least a.
In case of necessity, being used for nucleic acid molecules of the present invention can be optimized, so that the high level expression of target antigen (like the early stage polypeptide of HPV) to be provided in particular host cell or biology (for example human host cell or biology).The codon optimized general codons that replace with the coding same amino acid of one or more more frequent uses through one or more " natural " (for example HPV) codon with less use in the mammalian host cell carry out.This can realize through conventional mutagenesis or through chemical synthesising technology (for example producing nucleic acid).The part replacement there is no need to replace all natural codons, even because also can realize the expression that improves corresponding to the less son that accesses to your password.In addition, can produce some that use with the strict codon of deferring to optimization and depart from, be used to adapt to the introducing of restriction site.
The term " recombinant vector " that this paper uses refers to the carrier of virus and non-virus, comprises chromosome outer (like episome), multicopy and integrating vector (that is, being integrated in the host chromosome).It is especially important the expression vector that is used for Vectors in Gene Therapy (that is, can with the carrier of delivery of nucleic acids to host living beings) and is used for multiple expression system among the present invention.Suitable non-virus carrier comprises plasmid, pREP4 for example, pCEP4 (Invitrogene), pCI (Promega), pCDM8 (Seed, 1987, Nature329,840), pVAX and pgWiz (Gene Therapy System Inc; Himoudi etc., 2002, J.Virol.76,12735-12746).Suitable viral vectors can be from multiple different virus (for example retrovirus, adenovirus, AAV, poxvirus, herpesviral, measles virus, foamy virus etc.The term " viral vectors " that this paper uses comprises carrier DNA/RNA and by the virion of its generation.Viral vectors can have replication capacity, perhaps can in heredity, make it lose ability, thus become replication defective or duplicate impaired.The term that this paper uses " has replication capacity " and comprises and duplicates the viral vectors that selectivity and conditionality are duplicated, and they are transformed in specific host cell (like tumour cell) and duplicate better or copy choice.
In one aspect, be used for recombinant vector of the present invention and be recombinant adenoviral vector (summary is consulted " Adenoviral vectors for gene therapy ", 2002, D.Curiel and J.Douglas edit, Academic Press).It can be from various human or animal origin, and all can use from any serotype of adenoviral serotype 1 to 51.Particularly preferably be adenovirus hominis 2 (Ad2), 5 (Ad5), 6 (Ad6), 11 (Ad11), 24 (Ad24) and 35 (Ad35).These adenovirus can derive from American type culture collection, and (Md.), and existing lot of documents describes its sequence, tissue and production method, makes those skilled in the art can use them and (consults like US 6,133,028 for ATCC, Rockville; US 6,110, and 735; WO 02/40665; WO 00/50573; EP 1016711; Vogels etc., 2003, J.Virol.77,8263-8271).
Be used for adenovirus of the present invention and can have replication capacity.Multiple instance with adenovirus vector of replication capacity be easy to for those skilled in the art obtain (consult like Hernandez-Alcoceba etc., 2000, Human Gene Ther.11,2009-2024; Nemunaitis etc., 2001, Gene Ther.8,746-759; Alemany etc., 2000, Nature Biotechnology 18,723-727).For example, can from the wild-type adenovirus genome, transform them through following method: disappearance E1A CR2 domain (consulting) and/or natural E1 and/or E4 promoter are replaced with tissue, tumour or cell state specificity promoter (consult like US 5,998 like WO00/24408; 205, WO99/25860, US 5; 698; 443, WO00/46355, WO00/15820 and WO01/36650).
Alternatively, being used for adenovirus vector of the present invention can be (consulting like WO94/28152 of replication defect type; Lusky etc., 1998, J.Virol 72,2022-2032).Preferred replication-defective adenoviral vector be the E1 deficiency (consult like US 6,136,594 with US 6; 013,638), the E1 disappearance roughly extends to 3328 from 459; Or (sequence of people's 5 type adenovirus is disclosed in GenBank registration number M73260 and Chroboczek etc. roughly to extend to 3510 from 459; 1992, Virol.186,280-285).Can come further to improve clone's capacity through genomic other parts of deleted adenovirus (nonessential E3 district or other must E2, E4 district all or part of).Can (1996, J.Virol.70 4805-4810) saidly inserts nucleic acid through homologous recombination in any position of adenovirus vector like Chartier etc.For example, can the nucleic acid replacement E1 district of coding HPV-16 E6 polypeptide be inserted, and the nucleic acid of the HPV-16E7 polypeptide of will encoding replacement E3 district's insertion, or vice versa.
Another preferred aspect, being used for carrier of the present invention is poxvirus vector (consulting like " Viruses in Human Gene Therapy " Ed J.M.Hos such as Cox Carolina Academic Press).According to another embodiment preferred, it is selected from vaccinia virus, and suitable vaccinia virus includes but are not limited to Copenhagen strain (Goebel etc., 1990, Virol.179,247-266 and 517-563; Johnson etc., 1993, Virol.196,381-401), Wyeth strain and the highly attenuated virus that produces by their; Comprise MVA (summary is consulted Mayr, A., etc., 1975; Infection 3,6-14) and derivant (for example MVA bovine vaccine strain 575 (ECACC V00120707-US 6,913,752), NYVAC (consult WO 92/15672-Tartaglia etc.; 1992, Virology, 188,217-232).Can accurately identify 7 disappearance (I to VII) (Antoine etc. that in the MVA genome, exist to the mensuration of MVA genome complete sequence and with genomic relatively the making of Copenhagen VV; 1998; Virology 244; 365-396), wherein any one all can be used for inserting the nucleic acid of coding for antigens.This carrier also can derive from Poxviridae any other member, particularly fowl pox (for example TROVAC consults Paoletti etc., 1995, Dev Biol Stand., 84,159-163); Canary pox (ALVAC for example, WO 95/27780, Paoletti etc., 1995, Dev Biol Stand., 84,159-163); Pigeon variola; Swine pox etc.For example, those skilled in the art can be with reference to WO 9215672 (through with reference to incorporating this paper into), and it has been described based on poxvirus and has produced the expression vector that can express these heterologous nucleotide sequence (the particularly nucleotide sequence of coding for antigens).
According to specific embodiment, said virus can be the poxvirus with replication capacity, can have the vaccinia virus of replication capacity especially.In WO9531105 (for example product J X594, VV TK-GMCSF or JX963, VV TK-VGF-GMCSF), WO0073479, WO2009/065547, WO2009/065546, these viral instances are provided.
The basic fundamental of in the poxvirus genome group, inserting nucleic acid and expressing required associated adjustment element is described in (Paul etc., 2002, Cancer gene Ther.9,470-477 in the obtainable lot of documents of those skilled in the art; Piccini etc., 1987, Methods of Enzymology 153,545-563; US 4,769, and 330; US 4,772, and 848; US 4,603, and 112; US 5,100,587 with US 5,179,993).General through viral genome and the homologous recombination that has between the existing overlap between the plasmid that is inserted into nucleic acid (that is the insertion site of expectation) carry out.
The nucleic acid of code book invention antigen preferably inserts in the dispensable gene seat of poxvirus genome group, so that recombinant poxvirus still can be survived and still had infectivity.Nonessential region is the intergenic region of non-coding, or its inactivation or the disappearance significantly growth of infringement virus, any gene that duplicates or infect.It is also contemplated that and insert in the essential viral gene seat that as long as the defective function provides with trans, for example use auxiliary cell to provide, it has the complementary sequence corresponding to institute's deletion sequence in the poxvirus genome group in the production process of virion.
When using copenhagen vaccinia, antigen encoding nucleic acid preferably inserts (Hruby etc., 1983, Proc.Natl.Acad.Sci USA 80,3411-3415 in the thymidine kinase gene (tk); Weir etc., 1983, J.Virol.46,530-537).Yet other insert the site also is suitable, for example (Guo etc., 1989 in hemagglutinin gene; J.Virol.63,4189-4198), in the K1L locus, in the u gene (Zhou etc., 1990; J.Gen.Virol.71 2185-2190) or the left distal end of vaccinia virus gene group, has reported the multiple spontaneous or disappearance (Altenburger etc. that transform here in document; 1989, Archives Virol.105,15-27; Moss etc. 1981, J.Virol.40,387-395; Panicali etc., 1981, J.Virol.37,1000-1010; Perkus etc., 1989, J.Virol.63,3829-3836; Perkus etc., 1990, Virol.179,276-286; Perkus etc., 1991, Virol.180,406-410).
When using MVA, antigen encoding nucleic acid can insert any among the disappearance I to VII that has identified or insert the D4R locus, is preferred (Meyer etc., 1991, J.Gen.Virol.72,1031-1038 but insert among disappearance II or the III; Sutter etc., 1994, Vaccine 12,1032-1040).
When using fowlpox virus, although can consider to insert in the thymidine kinase gene, antigen encoding nucleic acid preferably imports the intergenic region (consulting like EP 314569 and US 5,180,675) between ORF 7 and 9.
According to a specific embodiments, said recombinant vector is recombinant plasmid dna or recombinant viral vector.
According to another specific embodiments, said recombinant viral vector is the recombinant vaccinia carrier.
According to another specific embodiments, said recombinant vaccinia carrier is the recombinant MVA carrier.
Preferably, be used for antigen encoding nucleic acid of the present invention and be being suitable for the form expressed at host cell or biology, this means that the nucleotide sequence of coding for antigens is in it expresses under the control of required one or more adjusting sequences in host cell or biology.The term " adjusting sequence " that this paper uses refers to any sequence; It allows, promotes or regulate the expression of nucleic acid in given host cell, comprise duplicate, transcribe, montage, translation, stability and/or one of nucleic acid or derivatives thereof (like mRNA) transported host cell.Skilled person in the art will appreciate that the selection of regulating sequence can be depending on various factors, for example the expression of host cell, carrier and expectation.The nucleic acid of coding for antigens effectively is connected with the expressed sequence that instructs this antigen nucleic acid in eukaryotic, to express.Expressed sequence is any modulability nucleotide sequence that the antigen nucleic acid that helps effectively being connected with it is effectively transcribed and translated, for example promoter sequence or promoter-enhancer combination.For example, expressed sequence can be the promoter of mammal or virus, for example composing type or inducible promoter.The composing type mammalian promoter includes but are not limited to the promoter of following gene: hypoxanthine phosphoribosyltransferase (HPRT), adenosine deaminase, pyruvate kinase, b-actin promoter and other constitutive promoters.The exemplary viral promotors of performance composing type function comprises as from following promoter in eukaryotic: cytomegalovirus (CMV), simian virus (for example SV40), papillomavirus, adenovirus, human immunodeficiency virus (HIV), Rous sarcoma virus, cytomegalovirus, moloney leukemia virus and other are retroviral longly terminally to repeat (LTR), and the thymidine kinase promoter of herpes simplex virus.Other constitutive promoters are known by those of ordinary skills.The promoter that can be used as expressed sequence of the present invention also comprises inducible promoter.Inducible promoter is expressed in the presence of inducer.For example, metallothionein promoter in the presence of some metallic ion by inducible transcription and translation.Other inducible promoters are known by those of ordinary skills.Usually, like needs, expressed sequence should comprise and relate separately to 5 ' initial non-transcribed and the 5 ' non-translated sequence of transcribing and translating, for example the TATA box, add cap sequence, CAAT sequence etc.Especially, these 5 ' non-transcribed sequences will comprise promoter region, and it comprises the promoter sequence that is used for the antigen nucleic acid of effective connection is transcribed control.As required, expressed sequence randomly comprises enhancer sequence or upper reaches activation subsequence.The preferred promoter that is used for poxvirus vector (seeing below) includes but are not limited to cowpox promoter 7.5K, H5R, TK, p28, p11 and K1L, and chimeric promoters and synthetic promoter between the early stage and late period poxvirus are like Chakrabarti etc. (1997; Biotechniques 23; 1094-1097), Hammond etc. (1997, J.Virological Methods 66,135-138) and Kumar and Boyle (1990; Virology 179, and is 151-158) said.
The promoter particular importance the present invention includes the constitutive promoter that instruction nucleic acid expresses and instructs and only in some host cell, express or respond to particular event or extrinsic factor (like temperature, nutrient interpolation, hormone or other parts) and expression promoter in many host cell types.Suitable promoter extensively is described in the document, what deserves to be mentioned is viral promotors, like RSV, SV40, CMV and MLP promoter.The preferred promoter that is used for poxvirus vector includes but are not limited to cowpox promoter 7.5K, H5R, TK, p28, p11 and K1L, and chimeric promoters and synthetic promoter between the early stage and late period poxvirus are like Chakrabarti etc. (1997; Biotechniques 23; 1094-1097), Hammond etc. (1997, J.Virological Methods 66,135-138) and Kumar and Boyle (1990; Virology 179, and is 151-158) said.
Skilled person in the art will appreciate that regulating element that control nucleic acid molecules of the present invention is expressed also can comprise is used for regulating following element: host cell or biology correctly initial, regulate and/or stop transcribing (like poly A transcription terminator), mRNA transportation (like the nuclear localization signal sequence), processing (like splicing signal), stability (like introne and non-coding 5 ' and 3 ' sequence), translation (like peptide signal, propetide, three leaders, ribosome bind site, Shine-Dalgamo sequence etc.).
Alternatively, be used at least a nucleic acid that recombinant vector of the present invention also can comprise at least a cell factor of encoding.Suitable cell factor include but are not limited to interleukin (like IL-2, IL-7, IL-15, IL-18, IL-21) and interferon (like IFN γ, INF α), preferred especially interleukin I L-2.When recombinant vaccine of the present invention comprised the nucleic acid of the express cell factor, said nucleic acid can be carried by the recombinant vector of one or more antigens of coding, is perhaps carried by the independently recombinant vector that can be identical or different source.
According to a most preferred embodiment, be used for all or part of and above listed at least a cell factor of recombinant vector of the present invention coding MUC1 antigen, and preferred interleukin, particularly IL2.Preferably, be used for recombinant vector of the present invention and be all or part of and above listed at least a cell factor of coding MUC1 antigen, and the MVA of preferred interleukin, particularly IL2.
The infectious viral particle that comprises above-mentioned recombinant viral vector can produce through conventional method.Illustrative methods may further comprise the steps:
A. viral vectors is introduced in the suitable clone,
B. cultivate said clone under proper condition, produce said infectious viral particle with permission,
C. from the culture of said clone, reclaim the infectious viral particle that produced and
D. the infectious viral particle that randomly purifying reclaimed.
The cell that is applicable to the adenoidism poisonous carrier is for example 293 cells, PERC6 cell, HER96 cell or WO 94/28152, and WO 97/00326, and US 6,127, disclosed cell in 175.
The cell that is applicable to the propagation poxvirus vector is the bird cell, the former generation CEF (CEF) that is most preferably prepared by the chicken embryo that derives from embryonated egg.
Infectious viral particle can reclaim or after cracking, from cell, reclaim (for example through chemical method, freeze thawing, osmotic shock, machinery shock, sonicated etc.) from culture supernatants.Virion can separate through continuous spot purifying round, then uses the technological purifying (chromatography, ultracentrifugation on cesium chloride or saccharose gradient) of this area.
If desired, according to the method for treatment of the present invention patient's human diseases or purposes (promptly comprising at least a immunogenicity of antigens composition) through using can with one or more conventional therapeutic modalities (for example radiation, chemotherapy and/or operation) Joint Implementation in selected patient.The selected patient that is used for of multiple therapy methods provides based on wideer intervention.In one embodiment, method or purposes of treating patient's human diseases according to the present invention can be prior to or subsequent to surgical intervention.In another embodiment, it can be prior to or subsequent to radiation therapy (for example γ radiation).Those skilled in the art can formulate easily suitable operable radiation treatment plan and parameter (consult like Perez and Brady, 1992, Principles and Practice of radiation Oncology, second edition, JB Lippincott Co; The suitable modification of using and change apparent to those skilled in the art.Again in another embodiment, the chemotherapy of method of the present invention or purposes and one or more medicines of use (for example conventional be used to treat or the medicine of prophylaxis of viral infections, pathologic conditions that virus is relevant, cancer etc.) is correlated with.
Therefore, the present invention relates to be used to improve the method for cancer patient's treatment, said cancer patient through benefiting from the chemotherapy of chemotherapeutant, said method comprising the steps of:
-in the patient crowd who forms by patient, select the patient with low IL10/IFN γ ratio,
-selected patient is used according to immunogenic composition of the present invention and chemotherapeutant.
Therefore, the present invention relates to be used to improve treatment cancer patient's method, said cancer patient through benefiting from the chemotherapy of chemotherapeutant, said method comprising the steps of:
-in from patient's biological sample (for example blood or blood plasma or serum), measure the level of IL10 and IFN γ,
-calculate IL10/IFN γ ratio and
-according to the present invention,, the patient is used said immunogenic composition if said patient has low IL10/IFN γ ratio.
According to an embodiment, before using said immunogenic composition, use said chemotherapeutant.
According to another embodiment, after using said immunogenic composition, use said chemotherapeutant.
According to another embodiment, when using said immunogenic composition, use said chemotherapeutant.
According to an embodiment, said chemotherapeutant is cis-platinum and/or gemcitabine, perhaps similar material.
The invention still further relates to the method for improving cytotoxic drug (being chemotherapeutant) or radiocurable cytotoxic effect, said method comprises using according to immunogenic composition of the present invention treats the patient who in the patient crowd who is made up of the patient with low IL10/IFN γ ratio, selects altogether.
In another embodiment, the purposes of method of the present invention or immunogenic composition is implemented according to causing the reinforcement therapeutic modality, and said initiation is strengthened therapeutic modality and comprised that sequentially using one or more triggering compositions strengthens composition with one or more.Triggering composition and the different carrier of the general use of reinforcement composition, it comprises or at least a common antigenic structure territory of encoding.At first use and cause immunogenic composition and give host living beings, then 1 day during the difference in Dec after, booster immunization originality composition is used to same host living beings.Method of the present invention can comprise sequentially uses triggering composition 1 time to 10 times, is then sequentially to use the reinforcement composition 1 time to 10 times.As required, injection interval was about 1 thoughtful June.In addition, triggering composition can or be used at identical position or at other position through different route of administration through identical route of administration with the reinforcement composition.
According to concrete embodiment, the clinical benefit of expection is to be independent of the immune response to vaccine that is shown.
According to a specific embodiments, the present invention relates to said method, wherein said human diseases is a cancer.
According to an embodiment preferred, said cancer is for example breast cancer, colon cancer, kidney, the carcinoma of the rectum, lung cancer, head and neck cancer, kidney, chromoma, laryngocarcinoma, oophoroma, cervical carcinoma, prostate cancer, non-small cell lung cancer, leukemia (haematological cancer), cancer of the stomach, myeloma.
According to a specific embodiments, the present invention relates to said method, wherein said human diseases is an infectious diseases.
According to an embodiment preferred, said infectious diseases is viral-induced disease, for example the disease of bringing out such as HIV, HCV, HBV, HPV.
In the another one embodiment; The purposes of all or part of immunogenic composition that comprises target antigen that is used to prepare medicine is provided; The human diseases that is used for particular patient group treatment patient, the patient among the wherein said crowd has low IL10/IFN γ ratio.
In the another one embodiment; The purposes of the immunogenic composition that is used to prepare medicine is provided; Be used for the human diseases of treating the patient at particular patient group induce immune response (being the immune response that is produced), wherein said crowd's patient has low IL10/IFN γ ratio.
In another embodiment; The purposes of the immunogenic composition that is used to prepare medicine is provided; Be used for the human diseases of inducing the immune response (being the immune response that is produced) at least a antigen to treat the patient in particular patient group, wherein said crowd's patient has low IL10/IFN γ ratio.
In another embodiment; The purposes of the immunogenic composition that is used to prepare medicine is provided; Be used for the human diseases of inducing the immune response (being the immune response that is produced) to target antigen to treat the patient in particular patient group, wherein said crowd's patient has low IL10/IFN γ ratio.
In another embodiment; The purposes of the immunogenic composition that is used to prepare medicine is provided; Be used for (promptly at the particular patient group induce immune response; The immune response that is produced) treat patient's human diseases, the immune response that wherein said crowd's patient has low IL10/IFN γ ratio and wherein said generation is an innate immune responses.
According to a particular, said " immune response that is produced " among the said patient crowd is to be directed against tumour specific antigen or tumor associated antigen and/or viral antigen.According to an embodiment, said " immune response that is produced " among the said patient crowd is to synantigen not.According to a specific embodiments, said " immune response that is produced " among the said patient crowd is be directed against MUC1 antigen all or part of.According to another specific embodiments, said " immune response that is produced " among the said patient crowd is the T cellullar immunologic response, and is preferably CD8+ (CTL) immune response.According to another specific embodiments; Said " immune response that is produced " among the said patient crowd is nonspecific immune response, or to the immune response of the antigen that is not included in the disease association in the bacterin preparation or to prior art the immune response of antigen of immeasurablel disease association.According to another specific embodiments, said " immune response that is produced " in said patient crowd is the stimulation of innate immune responses.
In animal or human's class biology, induce or ability that immune stimulatory is replied can use the multiple determination method of this area standard to estimate in external or body through using.Generality for the technology of the initial sum activation that can be used to estimate immune response is described, consult as Coligan etc. (1992 and 1994, Current Protocols in Immunology; J Wiley & Sons company limited writes, National Institute of Health).The measurement of cellular immunity can be carried out through following method: the effector cell through measuring by activation comprises those cell factor that is derived from CD4+ and CD8+T emiocytosis spectrums (for example quantitatively producing the cell of IL-10 or IFN γ through ELIspot); Through the active state (the T cell proliferating determining method of for example absorbing) of measuring immune effector cell, through the T lymphocyte (the for example peptide specific cracking in cytotoxicity assay) of mensuration antigen-specific in the patient of sensitization or through utilizing fluorescence MHC and/or peptide multimer (the for example tetramer) to detect T cells with antigenic specificity through classical [3H] thymine.Stimulate the ability of humoral response to measure through antibodies and/or combination competition (consult like Harlow, 1989, Antibodies, Cold Spring Harbor publishing house).Method of the present invention also can further be verified in the animal model of attacking with suitable tumor inducing agent (for example expressing the mouse tumour cell of MUC1) to confirm antitumor activity, to reflect to induce or strengthen anti-antigen immune response.
Therefore, the invention still further relates to, said method comprising the steps of through using the method that immunogenic composition prolongs the patient's who carries out human diseases such as treatment of cancer survival rate:
-in the patient crowd who forms by patient, select the patient with low IL10/IFN γ ratio,
-use said immunogenic composition to the patient of said selection.
The invention still further relates to through using the method that immunogenic composition prolongs the patient's who carries out human diseases such as treatment of cancer survival rate, said method comprising the steps of:
-in the patient, measure the level of IL10 and IFN γ,
-calculate IL10/IFN γ ratio and
If-said patient has low IL10/IFN γ ratio, use said immunogenic composition to the patient.
The invention still further relates to through using the method that immunogenic composition and chemotherapeutant (consulting above-mentioned) prolong the patient's who carries out human diseases such as treatment of cancer survival rate, said method comprising the steps of:
-in the patient, measure the level of IL10 and IFN γ,
-calculate IL10/IFN γ ratio and
If-said patient has low IL10/IFN γ ratio, use said immunogenic composition and chemotherapeutant to the patient.
According to another embodiment, the present invention relates to the purposes of IL10/IFN γ ratio as biomarker, be used to predict whether the patient is easy to produce preventative or therapeutic is replied through using immunogenic composition, preferably immune response.
More specifically; The present invention relates to the purposes of IL10/IFN γ ratio as biomarker; Be used to predict whether the patient is easy to produce preventative or therapeutic immunization is replied through using immunogenic composition; Wherein low IL10/IFN γ ratio shows that the prediction patient has producing preventative or therapeutic is replied, preferably the susceptibility that increases of immune response.
In other words; The present invention relates to the purposes of IL10/IFN γ ratio as biomarker; Being used for prediction patient after using immunogenic composition, whether to tend to survival longer, and wherein low IL10/IFN γ ratio shows the prediction patient and through the patient's survival rate longer than having with higher IL10/IFN γ ratio of treatment.
In other words; The present invention relates to the method that exsomatizes; Whether be used for prediction patient after using immunogenic composition tends to survive longer; Wherein method of testing comprises that step is in from patient's biological sample (for example blood or blood plasma or serum), to measure the level of IL10 and INF γ, calculates IL10/IFN γ ratio, and wherein low IL10/IFN γ ratio shows that the patient will have longer survival rate.
Therefore; The invention still further relates to the purposes of IL10/IFN γ ratio as biomarker, chemotherapeutant carries out producing preventative after whether chemotherapeutical patient is easy to using immunogenic composition or therapeutic immunization is replied (for example survival is longer) through benefiting to be used for prediction.
Therefore; The invention still further relates to the purposes of IL10/IFN γ ratio as biomarker; Chemotherapeutant carries out producing preventative after whether chemotherapeutical patient is easy to using immunogenic composition or therapeutic immunization is replied (for example survival is longer) through benefiting to be used for prediction, and wherein low IL10/IFN γ ratio shows that the patient estimates to have and replys the susceptibility of increase to producing preventative or therapeutic immunization.
Therefore, the present invention relates to be used to improve the method for cancer patient's treatment, said cancer patient through benefiting from the chemotherapy of chemotherapeutant, said method comprising the steps of:
-in the patient, measure the level of IL10 and IFN γ,
-calculate IL10/IFN γ ratio and
-if said patient has low IL10/IFN γ ratio according to the present invention, uses said immunogenic composition and chemotherapeutant to the patient.
The present invention also provides kit (i.e. test (companion test) on the same group), and it comprises the part of implementing methods described herein, and this is conspicuous in the embodiment that this paper provided.Kits of parts (kit of parts) or kit can comprise be used to collect with or measure the reagent of the serum levels of IL10 and IFN γ.This type of reagent can comprise antibody.Kit can also comprise the equipment that is used to collect and/or handle biological sample.Kit also possibly contain operation instructions, is used for cutoff value (opinion) and/or instructions that it is confirmed, and is used to explain the instructions that uses the data that kit obtained.
According to a specific embodiment, said kits of parts or kit can also comprise as disclosed above and/or as at the following disclosed immunogenic composition of embodiment part.
The present invention also provides computer program and/or algorithm; Be used to monitor clinical testing; The level of IL10 and IFN γ is measured this type of ratio and whether is higher or lower than threshold level with IL10 and IFN γ ratio, and/or recommended therapy is to improve patient's replying the immunotherapy treatment.Computer program or algorithm can provide with necessary hardware, and for example with the form of kit or device, it also can be accepted biological sample and measure IL10 and the level relatively of IFN γ and the ratio of calculating IL10 and IFN γ that wherein exists.Aforementioned calculation machine program and/or device possibly comprise that antibody offers doctor or clinical labororatory with suitable instructions and reagent.
The level of IL10 and IFN γ is producing suggestion to treating modification to improve the patient to the purposes in the algorithm of replying of treating through the immunotherapy of immune composition.
Described the present invention with illustrative approach, and should be appreciated that, used term is intended to use with illustrative approach, and unrestricted.Obviously, from above instruction, can obtain many modifications of the present invention and change.Therefore, should be appreciated that within the scope of the appended claims, the present invention can the mode different with the specific descriptions of preceding text implement.
The all complete clearly this paper of incorporating into of the disclosure of the patent that preceding text are quoted, publication and database all points out to incorporate into this paper separately as a reference equally as each single patent, publication or clauses and subclauses as a reference particularly.
Embodiment
Fig. 1: the survival curve that is described in the treatment of vaccine immunity in the lung cancer: before treatment, the patient has≤perhaps＞3.7 plasma IL-10/IFNg ratio
The 1st group: in patient, carry out vaccine (being immunogenic composition)+chemotherapy with low plasma IL-10/IFN γ ratio.Hang down plasma IL-10/IFN γ ratio to be defined as≤3.7.40 routine patients.Survival median=21.2 month
The 2nd group: in patient, carry out vaccine+chemotherapy with high plasma IL-10/IFN γ ratio.High plasma IL-10/IFN γ ratio is defined as＞and 3.7.21 routine patients.Survival median=5.6 month
Significant difference is through logarithm grade: p=0.007
O is complete+on inspection
Fig. 2: be described in chemotherapeutical survival curve in the lung cancer: before treatment, the patient has≤perhaps＞3.7 plasma IL-10/IFNg ratio
The 1st group: in patient, carry out chemotherapy with low plasma IL-10/IFN γ ratio.Hang down plasma IL-10/IFN γ ratio to be defined as≤3.7.57 routine patients.Survival median=10.8 month
The 2nd group: in patient, carry out chemotherapy with high plasma IL-10/IFN γ ratio.High plasma IL-10/IFN γ ratio is defined as＞and 3.7.11 routine patients.Survival median=8.4 month
Non-significant difference is through logarithm grade: p=0.92
O is complete+on inspection
In the middle of patient with IL10/IFNg pretreat ratio≤3.7; Those patients with TG4010+ chemotherapy treatment (survival median=21.2 month) are than separately with the patient of chemotherapy treatment (survival median=10.8 month) conspicuousness ground survival longer (p=0.03 is through log-rank test).The survival median had conspicuousness ground different in the middle of the patient who does not rely on plasma IL-10/IFN γ ratio: for the patient who treats with the TG4010+ chemotherapy 10.7 months; With for separately with the patient of chemotherapy treatment 10.3 months.
Embodiment 1:
Immunogenic composition, famous vaccine TG4010 unites with the standard chemical therapy and to be used to treat non-small cell lung cancer (NSCLC) patient.
TG4010 be the reorganization of not only having expressed IL2 but also expressing tumor related antigen MUC1 through modification virus Ankara (MVA) (consult Rochlitz etc., 2003, J.Gene Med., 5,690-699).
148 patients are accepted at random:
-only chemotherapy (per 3 the week the 1st day cis-platinum 75mg/m
2And the 1st day and the 8th day gemcitabine 1250mg/m
2, up to 6 circulations) (seminar 2) perhaps
-with the chemotherapy (seminar 1) of TG4010.
Per 6 weeks are estimated tumour (WHO standard).Terminal point is the existence (PFS) that the disease when June does not have deterioration, and total survival is intended to the treatment analysis.
Before the 1st day (treating first day) treatment, gather blood sample and transport immunization experiment chamber, center immediately to, separated plasma and refrigerated storage are up to analysis herein.
In the cell factor of centralab's evaluation plasma sample, use Luminex multiple analysis thing analytic system (Luminex mutli-analyte profiling system).
Fig. 1 has shown patient's [seminar 1 (TG4010+ chemotherapy)] (survival median=21.2 month) of ratio≤3.7 of the PC that before treatment, has interleukin 10/interferon gamma, and survival for more time than patient's (the survival median is 5.6 months) of ratio＞3.7 of the PC that before treatment, has interleukin 10/interferon gamma.
Data presentation among Fig. 2; Be based on the be situated between ratio＜3.7 of PC of plain 10/ interferon gamma of treatment proleukocyte and select patients' effectiveness to be limited to the patient who has accepted vaccine, because the patient that Fig. 2 is presented at the ratio that has the PC of interleukin 10/interferon gamma before the TG4010 treatment＜perhaps＞3.7 has identical survival expectation.
Claims (17)
1. be used for the whether stripped method to comprising that the methods of treatment of using immunogenic composition can therapeutic be replied of test patient, wherein method of testing comprises the steps:
-obtain biological sample from the patient;
-in said biological sample, measure the level of IL10 and IFN γ;
-calculating IL10/IFN γ ratio; With
-more said IL10/IFN γ ratio and threshold level, wherein low IL10/IFN γ ratio show that having low IL10/IFN γ ratio is that patient below 5 will produce preventative or therapeutic is replied to immunogenic composition.
2. the process of claim 1 wherein that said low IL10/IFN γ ratio is below 4.
3. claim 1 or 2 method, wherein said methods of treatment is the treatment method for cancer.
4. the method for any aforementioned claim is wherein used
LuminexSaid IL10/IFN γ ratio is measured in technology or enzyme linked immunosorbent assay (ELISA).
5. the method for any claim is wherein through using IL10 and the said IL10/IFN γ of the specific TPPA of IFN γ ratio respectively.
6. the method for any aforementioned claim, wherein said biological sample is selected from total blood sample, blood plasma or serum.
7. the method for any aforementioned claim, wherein said immunogenic composition contains at least one recombinant vector, its at least one heterologous nucleotide sequence of expression in vivo all or part of.
8. the method for claim 7, wherein said recombinant vector is a viral vectors.
9. claim 7 and 8 each methods, wherein said viral vectors has replication capacity.
10. claim 7 and 8 each methods, wherein said viral vectors is a replication defect type.
11. each method of claim 7 to 10, wherein said viral vectors is an adenovirus.
12. each method of claim 7 to 10, wherein said viral vectors is the bovine vaccine carrier.
13. each method of claim 7 to 10, wherein said viral vectors is the MVA carrier.
14. the method for any aforementioned claim, wherein said patient is the patient with the chemotherapeutant treatment.
15.IL10/IFN the γ ratio as the purposes of biomarker, is used to predict whether the patient is easy to produce preventative or therapeutic is replied through using immunogenic composition.
16. whether test patient kit to comprising that the methods of treatment of using immunogenic composition can therapeutic be replied, wherein kit comprises:
-be used at the antibody of measuring the level of IL10 and IFN γ from patient's biological sample; With
-being used to explain that the instructions of the data of acquisition, said instructions described low IL10/IFN γ ratio and shown that the patient will produce preventative or therapeutic is replied to immunogenic composition, wherein low ratio is to be less than about 5 ratio.
17. be used to predict whether the patient is easy to the longer stripped method of surviving after using immunogenic composition, and wherein method of testing comprises step:
-obtain biological sample from the patient;
-in said biological sample, measure the level of IL10 and IFN γ;
-calculating IL10/IFN γ ratio; With
-more said IL10/IFN γ ratio and threshold level, wherein low IL10/IFN γ ratio show that having low IL10/IFN γ ratio is that patient below 5 will have longer survival rate.
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| US20140244556A1 (en) * | 2013-02-27 | 2014-08-28 | Abdul Saleh | Methods for and apparatus generating automated pharmaco genetics correlation |
| EP3011059B1 (en) | 2013-06-20 | 2019-02-06 | Immunexpress Pty Ltd | Biomarker identification |
| DK3103046T3 (en) | 2014-02-06 | 2020-06-02 | Immunexpress Pty Ltd | BIOMARKER SIGNATURE PROCEDURE AND DEVICES AND KITS THEREOF |
| FR3072973B1 (en) * | 2017-10-26 | 2022-02-11 | Univ Pierre Et Marie Curie Paris 6 | PSEUDO-VIRAL PARTICLES USEFUL FOR TREATING IMMUNE DYSFUNCTION |
| RU2705398C1 (en) * | 2018-08-17 | 2019-11-07 | федеральное государственное бюджетное образовательное учреждение высшего образования "Новосибирский государственный медицинский университет" Министерства здравоохранения Российской Федерации (ФГБОУ ВО НГМУ Минздрава России) | Method for prediction of the effectiveness of the agent for increasing the high-differentiated cells in mammary adenocarcinoma and the composition for its implementation |
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| EP2452194A1 (en) | 2012-05-16 |
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| EP2452194B1 (en) | 2015-11-11 |
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| US9261512B2 (en) | 2016-02-16 |
| HK1165206A1 (en) | 2012-09-28 |
| AU2010270313B2 (en) | 2014-05-22 |
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| RU2552292C2 (en) | 2015-06-10 |
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| TW201105970A (en) | 2011-02-16 |
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